Parkinson's disease (PD) is a neurodegenerative disorder with a hallmark of dopamine neuron degeneration in the Substantia Nigra pars compacta (SNpc), resulting in cardinal motor dysfunctions: resting tremor, bradykinesia (slowness of voluntary movement), muscular rigidity, and gait instability. SNpc dopamine neurons project heavily to the striatum, the main input nucleus of the basal ganglia. Dopamine depletion is thought to shift the balance between two antagonistic striatal output pathways through distinct dopamine receptors on the two populations of projecting medium spiny neurons, which results in an overall reduction in the cortical control of motor functions. In addition, dopamine depletion results in an upregulation of cholinergic tone by modulating cholinergic interneurons, and the imbalanced dopamine-acetylcholine interaction has also been suggested to be critical in PD pathophysiology. Anti-cholinergic drugs, the only available drugs for PD before the development of levodopa treatment in the 1970s, remain to be in clinical use today. Newer therapies such as deep brain stimulation (DBS) highlight the fact that PD involves neural network pathology. Intracranial recordings in PD patients revealed exaggerated oscillations in the cortical-basal ganglion circuit at beta frequencies, 11-30 Hz. Exaggerated beta oscillations closely parallel key PD motor deficits, and are largely suppressed by effective dopamine replacement treatment or DBS. Together, these evidences established a clear link between beta oscillations within the cortical-basal ganglia-thalamic network and PD motor symptoms. However, it remains unknown whether the exaggerated beta oscillation is the cause or a correlate of motor deficits, and where and how beta oscillations arise in PD. Our previous studies combining mathematical and pharmacological approaches have demonstrated that the striatum neural network is capable of generating beta oscillations upon upregulation of striatal acetycholine. Here, we aim to test the novel hypothesis that cholinergic over-activation in the Parkinsonian striatum plays a key role in producing pathological beta oscillations, and beta oscillations play a causal role in PD motor pathology. This novel hypothesis directly links dopamine induced cholinergic malfunction to neural circuit pathology and motor deficits. Because of the explorative nature of this project, we feel that the R21 funding mechanism is most appropriate for this project at this stage. PUBLIC HEALTH RELEVANCE: Parkinson's disease, a neural degenerative disorder, affects over 1 million patients in the US alone, with more than 50,000 newly diagnosed patients each year. This research seeks to understand the neural network mechanisms of pathophysiology in Parkinson's disease.